CD25-mediated feedback control of BCR-signaling and its oncogenic mimics

项目摘要 B细胞严重依赖于来自功能性B细胞受体（BCR）的持续生存和增殖信号。 同样，在约50%的B细胞恶性肿瘤中，肿瘤克隆由致癌BCR模拟物驱动。致癌 BCR依赖性增殖和存活信号的模拟物包括BCR-ABL 1（Ph+ ALL）、病毒癌蛋白（例如， EBV）、RAS和NF-κ B途径激活病变（霍奇金淋巴瘤、PMBL、ABC-DLBCL、毛细胞 白血病、Waldenström巨球蛋白血症）。在初步研究中，我们发现CD 25选择性地表达于 由致癌BCR模拟物驱动的恶性B细胞克隆。而CD 25作为T细胞上的IL 2受体β链发挥作用， 细胞，我们最近发现CD 25是BCR信号传导和致癌BCR的关键反馈调节因子。 人B细胞肿瘤中的模拟物。遗传学实验表明，CD 25对B细胞的启动至关重要 白血病和淋巴瘤。表面表达由BTK的活性快速诱导， PKC位于BCR的下游，并在转录水平上被FOXM 1和NF-κ B B诱导。CD 25招募 抑制复合物，以减少和重新校准BCR信号传导或致癌模拟 BCR信号传导。对三个临床队列的分析显示，CD 25的高表达水平与以下因素相关： 各种B细胞恶性肿瘤的临床结果较差。虽然CD 25表达与耐药性有关， 抑制CD 25或使CD 25依赖性反馈控制失效使多种B细胞恶性肿瘤对 常规药物治疗。 基于这些和其他发现，我们提出三个目标：（1）阐明CD 25调节的机制，（2） 探索CD 25介导的反馈控制的药理学颠覆的有用性和（3）靶向 通过CART 25细胞和作为治疗佐剂的抗体-药物缀合物（ADC）根除CD 25+细胞。

PROJECT SUMMARY B cells critically depend on continuous survival and proliferation signals from a functional B cell receptor (BCR). Likewise, in ~50% of B cell malignancies, the tumor clone is driven by an oncogenic BCR-mimic. Oncogenic mimics of BCR-dependent proliferation and survival signals include BCR-ABL1 (Ph+ ALL), viral oncoproteins (e.g. EBV), RAS- and NF-B-pathway activating lesions (Hodgkin's lymphoma, PMBL, ABC-DLBCL, hairy cell leukemia, Waldenström's macroglobulinemia). In preliminary studies, we found that CD25 is selectively expressed on malignant B cell clones driven by oncogenic BCR-mimics. While CD25 functions as IL2 receptor -chain on T cells, we recently discovered that CD25 is a critical feedback regulator of BCR signaling and oncogenic BCR- mimics in human B cell tumors. Genetic experiments demonstrated that CD25 is critical for the initiation of B cell leukemia and lymphoma in transplant recipients. Surface expression is rapidly induced by activity of BTK and PKC downstream of the BCR and induced by FOXM1 and NF-B at the transcriptional level. CD25 then recruits an inhibitory complex to the cell membrane to reduce and recalibrate BCR signaling or oncogenic mimicry of BCR-signaling. Analysis of three clinical cohorts revealed that high expression levels of CD25 are associated with poor clinical outcome in various B cell malignancies. While CD25 expression is associated with drug-resistance, inhibition of CD25 or disabling of CD25-dependent feedback control sensitizes multiple B cell malignancies to conventional drug-treatment. Based on these and other findings, we propose three Aims to (1) elucidate mechanisms of CD25 regulation, (2) explore usefulness of pharmacological subversion of CD25-mediated feedback control and (3) targeted eradication of CD25+ cells by CART25 cells and antibody-drug conjugates (ADC) as therapeutic adjuvant.